A review on botanicals with wound healing activity for pemphigus vulgaris: perspective of traditional Persian medicine and conventional medicine

Objective: As a rare autoimmune disease, pemphigus vulgaris has a poor prognosis especially in lack of proper medical support. This blistering disease involves both the skin and mucus membranes. The challenge is improving the healing process of skin lesions of which, superimposed infections are among the main causes of the disease mortality. Accordingly, we aimed to assess the treatment options suggested by traditional Persian medicine (TPM) and compare them with current findings. Materials and Methods: We studied the main clinical and pharmaceutical textbooks of TPM (Kitāb al-hāwīfī al-tibb, the Canon of Medicine, Eksir-e-Aazam, Tuhfat al-mu'minīn, Makhzan al-adviyah (focusing on the skin chapter and respective herbal remedies for the inflamed skin and ulcers. Additionally, scientific databases such as PubMed, Science direct, Scopus, and Google Scholar were searched for the current pharmacological evidence. In the studied books, the term “hot ulcers” was found close to what is known as “Pemphigus vulgaris”. Results: Reported medicinal herbs possess anti-inflammatory, antioxidant, wound healing, and antibacterial activities reported by recent studies. Therefore, they could be introduced as novel natural remedies for pemphigoid wounds. Conclusion: Taken as a whole, the review of traditional remedies for hot ulcers in Persian medical and pharmaceutical literature may open a new window toward developing new topical treatments for this disease.


Introduction
Pemphigus vulgaris (PV) is a rare blistering autoimmune disease of the skin and mucus membranes. It is caused by autoantibodies producedagainst antigens on the surface of keratinocytes (Kershenovich et al., 2014). There is no general agreement about the related treatment strategies. Treatment approaches mostly include establishment of disease remission in addition to effective control of it (Martin et al., 2011). These strategies are essentially conducted by systemic administration of corticosteroids. However, the undesirable side effects of these medicaments are often mentioned as the most frequent causes of morbidity and mortality (Poulin et al., 1984). Most important causes of death are: opportunistic superimposed infections, complications of long-term and high-dose usage of corticosteroids, and prolonged consumption of immune suppressant medicines (Ahmed, 2001).
Several investigations have been conducted on supplementary and natural medicaments to reduce the dose and consequently complications of the applied steroids (Ahmed, 2001;Mutasim et al., 2005;Poulin et al., 1984). Of course, it should be noticed that even such medicines may cause life-threatening infections as well as increased risk of infertility and cancer (Mutasim et al., 2005). Topical treatment approaches to PV are considered as supplementary therapy to systemic treatment. These strategies are believed to be effective via prevention of infection and promotion of re-epithelialization of the eroded skin (Ruocco et al., 2013).
In PV, skin lesions are among the most important sources of infection. In this regard, any topical treatment shortening the healing time of lesions and reducing the total drug dosage could be clinically reasonable (Tabrizi et al., 2007).
Herbal pharmacotherapy has a long history in traditional Persian medicine (TPM) (Golshani SA et al., 2015). With reference to the remaining documents of TPM which has been attributed to Unani medicine in Harrison's Principles of Internal Medicine (Kasper et al., 2015) and in line with our previous investigations (Atarzadeh et al., 2016 (a) and (b)), the present study aimed at compiling a framework encompassing pharmacological and medical aspects of PV management in the light of TPM insights.

Methodology
Initially, recent etiopathogenesis findings on PV emerged in PubMed, Scopus and Science direct databases were studied. The traditional term of "hot ulcer" was found very close to PV with regard to the clinical manifestations. Accordingly, description and etiological aspects of this disorder as well as pharmaceutical managements were derived from main medical and pharmaceutical manuscripts of TPM from the 10 th to 18 th centuries AD.  (Shīrāzī, 2009;Tunakābunī, 2007). Medical literature was the Canon of Medicine by Avicenna (MS A 53, NLM, NLM Microfilm Reel: FILM 48-122 no. 5; 2 nd volume, 980-1037 AD) (4 th volume) and Eksir-e-Aazam (The Great Elixir written by Mohammad Azam Khan 1814-1902 AD) (Azam Khan, 2008;Ibn Sina, 1988).
Finally, to make a conclusion on collected medicaments, the results were compared and confirmed with the recent evidence on the herbs' related pharmacological activities and therapeutic mechanisms of action.

Etiologic factors involved in the pathogenesis of PV
The main pathologic process in PV is "acantholysis" which is the result of cells detachment due to the destruction of their adhering glue, desmoglein by autoantibodies (Shah and Parmar, 2016). Although the cause of this autoimmune disease is originally unknown, some factors have been recognized to be involved in pathogenesis of the disease. For instance, there are circulating IgG autoantibodies directed against the normal desmogleins(Dsg) (a cell-to-cell adhesion molecule) (Kershenovich et al., 2014). T helper (Th) cells are also involved in the pathogenesis of PV. The role of autoreactive T cells in induction and regulation of antibody production has been suggested in a recent study (Veldman et al., 2004). Moreover, contribution of interlukin-4 (IL-4), IL-5, IL-6 and IL-10 to the pathogenesis of PV suggests Th2 involvement (Okon and Werth, 2014). Oxidative stress is another issue which is considered to be involved in the etiology and pathogenesis of PV. In addition, there is a significant correlation between serum oxidative stress marker level and serum anti-desmoglein antibody level in PV (Abida et al., 2012).

Traditional approach to ulcer
"Wound" and "ulcer" are comprehensively outlined in the Canon of medicine with the special term of "jerahat" and "gharhe". Ulcers may be hard or soft, hot or cold, septic or aseptic. Some have discharge but some do not, and finally they may be easily healed or may be difficult to treat. According to the TPM, "gharhe" is divided into hot and cold types. Cold ones have a broad base and white color, with minimal itching; in contrast, hot types are sharp with red base, itching, burning sensation, and irritation (Azam Khan, 2008;Ibn Sina, 1988). Pemphigus wounds are irritating with burning sensation, sometimes are itching, with prolonged healing time, and probably have superimposed infection (Mutasim et al., 2005). Although there may not be a distinct entity in TPM that could be fully attributed to PV, the aforesaid description seems to be relevant with hot ulcers in TPM sources. In other words, PV could be generally considered as a hot inflamed ulcer in TPM categorization of ulcers. Various natural topical remedies have been used in TPM for hot ulcer (Atarzadeh et al., 2016 (b)). These remedies which have been used for many years by Iranian physicians are summarized in Table 1 ( Azam Khan, 2008;Ibn Sina, 1988;Shīrāzī, 2009;Tunakābunī, 2007). In addition, in vitro and in vivo studies on plants used for hot ulcer healing in the studied ancient books are cited in Table 2.

Discussion
Prolonged wound healing process of pemphigus erosions in addition to the associated pain, discomfort, and cosmetic problems are important determining factors in the duration of hospitalization and risk of secondary infections (Ali et al., 2006). Skin lesion is one of the most important sources of infection. For that reason, using local treatment, decreasing healing time of lesions, and reducing the total dosage of drugs are reasonable strategies (Tabrizi et al., 2007). Clinical evidence about proper interventions for PV is scant and additional research is needed (Kasperkiewicz et al., 2012). Nowadays, Complementary and Alternative Medicine (CAM) has become more popular in different societies (Danish et al., 2011) and there is an increasing trend in its integration with healthcare systems. In this regard, our primogenitor has made a lot of discoveries about the healing effects of plants through trial and error (Jaladat et al., 2015) that could be helpful even inmodern-day applications.
Table1. Medicaments used for wound healing in hot ulcer and their underlying mechanisms of action.

Scientific name Traditional name
Part used Application in Traditional medicine Activities * Ref.
In TPM sources, many medicinal herbs have been mentioned for wound healing. Some of these herbs such as Portulacaoleracea L., Plantago ovata Forssk. and Plantago major L. have mucilaginous characteristics and tissue regenerating ability andhave been used for hot swelling and hot ulcer topically. Plantago major L., for instance, could beapplied for removing the pus out of the infectedwound; thus,it is useful for burns and skin diseases. Portulaca oleracea L. and Plantago ovata Forssk. with rose oil are also beneficial for burns and hot ulcers (Shīrāzī, 2009).
Plantago major L. is a very effective remedy for superficial wounds. Its aqueous extract has shown wound healing effects in rats. Mechanism of action of its wound healing activity is related to its antioxidant properties (Mahmood and Phipps, 2006).
It has been suggested that treatment of white Swiss mice skin wounds with fresh homogenized crude extract of Portulaca oleracea has accelerated the wound healing process (Rashed et al., 2003).
It is to be mentioned that almost every herb proposed in TPM sources for hot ulcer treatment, has anti-inflammatory, antioxidant and wound-healing activities which have been shown to be beneficial in treatment of Pemphigus lesions, in recent studies. Moreover, they have antibacterial activity which could accelerate the wound healing process in infected wounds (Tables  1 and2).
As the main limitation of our study, we only considered those herbal remedies with good levels of evidence reported byin vivo and/or in vitro wound healing investigations.

Conclusion
In this review, we aimed at summarizing the approach of Persian medicine toward wound healing and particular herbs that can be used for Pemphigus ulcers reepithelialization as a complementary treatment.
In general terms, reviews on Persian medicinal herbs could pave the way for development of new herbal-based formulations for better management of Pemphigus lesions. While basic research provides data about wound-healing and the favorable effects of some herbs or herbal compounds, well-designed clinical trials should also be considered in the future. Antibacterial activity and composition of the essential oils of Eucalyptus camaldulensis Dehn. and Myrtus communis